RELATIONSHIP BETWEEN AUC of 5'-DFUR AND TOXICITY OF CAPECITABINE, FLUOROPYRIMIDINE CARBAMATE ANALOGS, AND 5'-DFUR IN MONKEYS, MICE, AND RATS

Abstract

-Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N 4 -pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/ kg and the AUCs of 5'-DFUR were approximately 40 to 60 μg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 μg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 μg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 μg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.

Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans - toxicological implications

“…The histopathological changes of small and large intestines treated with capecitabine in mice at 1.1 and 2.2 mmol/kg/day and monkeys at 0.5 and 1.0 mmol/kg/ day for 4 weeks and the toxicokinetics are summarized in Table 4 (data are from Shindoh et al, 2006). The systemic exposure of 5'-DFUR AUC was almost the same at 2.2 mmol/kg in mice and 0.5 mmol/kg in monkeys.…”

“…In the case of capecitabine, as it likely passes through the intestinal mucosa as an intact molecule, production of 5-FU in intestinal mucosa is thought to be lower than with 5'-DFUR and therefore may induce lower toxicity in the intestine. We have reported that the toxicity of capecitabine in monkeys was reduced compared with that of 5'-DFUR based on mmol/kg dose and AUC of 5'-DFUR (Shindoh et al, 2006).…”

Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030)

“…A significantly higher DFUR AUC was found in females; however, this did not lead to a difference in circulating 5FU. One study reported a correlation between DFUR AUC with toxicities in animals, but these findings were not affirmed in humans (Shindoh et al , 2006). …”

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity

“…The repetitive oral administration of capecitabine plus oxaliplatin (XELOX) regimen is a standard treatment for CRC similar to the FOLFOX and FOLFIRI regimens (Watanabe et al, 2015). Capecitabine is sequentially converted to 5-FU via a three-step enzyme activation process in the liver and tissues (Desmoulin, Gilard, Malet-Martino, & Martino, 2002;Shindoh et al, 2006;Shindoh, Nakano, Yoshida, & Ishigai, 2011). First, capecitabine is converted to 5′deoxy-5-fluorocytidine (5′-DFCR) by carboxylesterase (CES), mainly in the liver.…”